Intestinal Lipid Processing, Bile Acid Metabolism, and Pancreatic Islet Function

肠道脂质加工、胆汁酸代谢和胰岛功能

• 批准号: 10339427
• 负责人: Chi- Liang Eric Yen
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-23 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339427
• 关键词: 2-acylglycerol O-acyltransferase; ASBT protein; Acyl Coenzyme A; Affect; Alpha Cell; Antibiotics; Apical; B-Lymphocytes; Beta Cell; Bile Acids; Cecum; Chemicals; Communication; Development; Diabetes Mellitus; Diabetic mouse; Diet; Dietary Fats; Digestion; Disease; Energy Metabolism; Environment; Enzymes; Epidemic; Escherichia coli; Exhibits; Failure; Fatty acid glycerol esters; GCG gene; GLP-I receptor; Genes; Germ-Free; Goals; Health; Health Care Costs; Healthcare; Hormones; Human; Hydrolase; Hyperglycemia; Insulin; Insulin Resistance; Intervention; Intestines; Islets of Langerhans; Isotopes; Knowledge; Life; Ligands; Link; Lipids; Macronutrients Nutrition; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolism; Molecular; Morphology; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Pancreas; Pathway interactions; Patients; Pharmacologic Substance; Physiological; Plasma; Predisposition; Prevalence; Prevention; Process; Receptor Signaling; Reporting; Research; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Societies; Sodium; Streptozocin; Structure of alpha Cell of islet; Structure of beta Cell of islet; Taurocholic Acid; Testing; Therapeutic Intervention; Tissues; Toxin; Tracer; Triglycerides; United States; Ursodeoxycholic Acid; Wild Type Mouse; Work; absorption; bile acid metabolism; bile salts; care burden; combat; endoplasmic reticulum stress; energy balance; feeding; glucagon-like peptide 1; glycemic control; gut microbiota; improved; inhibitor; insight; insulin secretion; islet; microbial; muricholic acid; novel; obesity treatment; overexpression; pancreatic islet function; pancreatic juice; preservation; prevent; preventive intervention; productivity loss; proglucagon; protective effect; receptor; receptor-mediated signaling

The prevalence of diabetes has reached epidemic proportions in the United States, gravely afflicting patients and burdening societies with productivity loss and health care costs. Diabetes is characterized by a reduction in beta cell mass in the pancreas, or a failure of beta cells to secrete enough insulin to fully compensate for insulin resistance. Augmenting or preserving functional beta cell mass is an attractive objective for preventing or treating diabetes; however, we have insufficient intervention targets. The long-term goal of our research is to better understand how intestinal lipid processing controls systemic metabolism and explore intervention targets to combat metabolic diseases. We have reported that acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) mediates intestinal fat absorption and regulates systemic energy balance. Although mice lacking a functional MGAT2 gene (Mogat2–/–) or lacking MGAT2 specifically in the intestine absorb normal amounts of dietary fat, they exhibit delayed fat absorption, increased energy expenditure, and resistance to obesity and related disorders. Intriguingly, we found that loss of MGAT2 protects mice against chemically- and genetically-induced diabetes by preserving functional beta cell mass. Associated with the protection, Mogat2–/– mice have increased plasma bile acids, known to have potent metabolic effects as ligands for membrane and nuclear receptors that regulate metabolism. Further, increasing plasma bile acids – by feeding mice ursodeoxycholic acid, treating mice with broad-spectrum antibiotics, or raising mice germ-free– is sufficient to protect functional beta cell mass against the beta-cell toxin, streptozotocin. Intriguingly, we also found reduced bile salt hydrolase (BSH) activity in cecum, where most gut microbiota reside, and increased GLP1 in pancreatic alpha-cells. To understand the physiological and molecular mechanisms underlying MGAT2 deficiency-mediated protection, we propose here to rigorously test our overarching hypothesis that that loss of intestinal MGAT2 (1) decreases microbial BSH activity, which (2) enhances reabsorption through the apical sodium-dependent bile salt transporter (ASBT), leading to (3) increased GLP1 secretion from pancreatic a-cells that induces GLP1 receptor (GLP1r)-signaling in b-cells, and thereby protects pancreatic islet function. In Aim 1, we will determine if a reduction in BSH activity is necessary and/or sufficient to increase plasma bile acids and protect mice again beta cell insults. In Aim 2, we will determine if loss of MGAT2 enhances re-absorption of bile acids and if the process requires ASBT. In Aim 3, we will determine if GLP1 produced in alpha cells and if GLP1 receptors on beta cells are required for the effects of MGAT2 deficiency. Our proposed work represents essential steps to elucidate novel pathways that link intestinal lipid processing and bile acid metabolism with pancreatic islet function. Our findings will describe a novel example of interorgan communication that controls systemic metabolism setting the stage for targeting MGAT2 inhibition to combat diabetes by decreasing bacterial bile salt hydrolase, increasing conjugated primary bile acids, and modulating intra-islet signaling.

糖尿病的流行在美国已经达到流行病的程度，严重地折磨患者并使社会负担生产力损失和医疗保健费用。糖尿病的特征在于胰腺中β细胞质量的减少，或者β细胞不能分泌足够的胰岛素以完全补偿胰岛素抵抗。增加或保留功能性β细胞质量是预防或治疗糖尿病的一个有吸引力的目标;然而，我们的干预目标还不够。我们研究的长期目标是更好地了解肠道脂质加工如何控制全身代谢，并探索对抗代谢性疾病的干预目标。我们已经报道了酰基辅酶A：单酰基甘油酰基转移酶2（MGAT 2）介导肠道脂肪吸收和调节全身能量平衡。尽管缺乏功能性MGAT 2基因（Mogat 2-/-）或在肠道中特异性缺乏MGAT 2的小鼠吸收正常量的膳食脂肪，但它们表现出延迟的脂肪吸收、增加的能量消耗以及对肥胖和相关疾病的抵抗力。有趣的是，我们发现MGAT 2的缺失通过保留功能性β细胞群来保护小鼠免受化学和遗传诱导的糖尿病。与保护相关，Mogat 2-/-小鼠具有增加的血浆胆汁酸，已知其作为调节代谢的膜和核受体的配体具有有效的代谢作用。此外，增加血浆胆汁酸-通过喂养小鼠熊去氧胆酸，用广谱抗生素治疗小鼠，或无菌饲养小鼠-足以保护功能性β细胞群免受β细胞毒素，链脲佐菌素的侵害。有趣的是，我们还发现盲肠中胆盐水解酶（BSH）活性降低，大多数肠道微生物群驻留在盲肠中，胰腺α细胞中GLP 1增加。为了了解MGAT 2缺陷介导的保护作用的生理和分子机制，我们在此提出严格检验我们的总体假设，即肠道MGAT 2的缺失（1）降低微生物BSH活性，（2）通过顶端钠依赖性胆盐转运蛋白（ASBT）增强重吸收，导致（3）胰腺a细胞的GLP 1分泌增加，其诱导b细胞中的GLP 1受体（GLP 1 r）信号传导，从而保护胰岛功能。在目标1中，我们将确定BSH活性的降低是否是必要的和/或足以增加血浆胆汁酸并再次保护小鼠β细胞损伤。在目标2中，我们将确定MGAT 2的丢失是否会增强胆汁酸的重吸收，以及该过程是否需要ASBT。在目标3中，我们将确定GLP 1是否在α细胞中产生，以及β细胞上的GLP 1受体是否是MGAT 2缺乏的影响所必需的。我们提出的工作是阐明肠道脂质加工和胆汁酸代谢与胰岛功能联系的新途径的重要步骤。我们的研究结果将描述一个新的器官间通讯的例子，控制全身代谢，为靶向MGAT 2抑制，以打击糖尿病，通过减少细菌胆盐水解酶，增加共轭初级胆汁酸，调节胰岛内信号传导。